Matt Hoffman, Senior Editor for NeurologyLive, has covered medical news for MJH Life Sciences, NeurologyLive’s parent company, since 2017. He hosts the Mind Moments podcast. Follow him on Twitter 

Matt Hoffman

Yumanity Therapeutics recently announced several updates related to its lead clinical-stage therapeutic development program for its investigational Parkinson disease agent, YTX-7739, including the results of a single ascending dose study, the completion of enrollment in a multiple ascending dose study, and the initiation of a phase 1b study.

YTX-7739 is a small molecule stearoyl-CoA desaturase (SCD) inhibitor that is designed to modulate an upstream process in the alpha-synuclein pathological cascade. According to Yumanity, it has been shown to rescue or prevent toxicity in preclinical models, giving the company reason to assess the potential utility of YTX-7739 in Parkinson disease.

“YTX-7739 is a novel small molecule SCD inhibitor, which can be administered orally and was shown to be brain penetrant in preclinical models. We have completed the single ascending dose (SAD) study in healthy volunteers, which provides early evidence of the drug candidate’s safety and tolerability profile,” Brigitte Robertson, MD, chief medical officer, Yumanity Therapeutics, said in a statement. “We look forward to reporting on the data from the ongoing Multiple Ascending dose (MAD) study in healthy volunteers and the preliminary results of our first clinical trial in patients with Parkinson’s disease, later this year. We wish to also thank our investigators, their staff, study volunteers and patients for their dedication in continuing this important research through the challenges of the COVID-19 pandemic.”

Yumanity announced the initiation of a placebo-controlled, randomized, double-blind, MAD phase 1b study of YTX-7739 in patients with Parkinson disease.

That study is anticipated to include 30 individuals and will assess the safety and tolerability of the therapy, as well as pharmacokinetic and pharmacodynamic parameters including potential biomarkers of SCD activity and target engagement in the CSF, plasma, and other fluids or tissues. The preliminary results of the phase 1b study are expected to read out by mid-year 2021.

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The phase 1 SAD study of YTX-7739 included 56 healthy volunteers aged 19 to 39 years (male, n = 22; female, n = 34) who were administered single doses of the agent ranging from 5 mg to 400 mg. The results of the SAD study supported progression to the MAD study.

Of those in the SAD study, 40 participated in the placebo-controlled, randomized, double-blind portion of the study, which consisted of 7 cohorts with 8 subjects each, randomized to either YTX-7739 or placebo in a 6:2 ratio. Two of those cohorts, including 16 patients, featured administration of YTX-7739 with food. Additionally, 2 cohorts of 8 subjects each were included in an open-label fashion to further inform dose selection for the MAD study.

Ultimately, the SAD study identified no safety concerns, and the Yumanity therapy was considered well-tolerated. Most adverse events (AEs) were deemed mild or moderate in severity. In tandem with a favorable pharmacokinetic profile in the fed state, the half-life of the therapy supports the notion that low daily doses administered with food can sustain the targeted range of drug exposure.

As well, plasma concentrations in the study exceeded levels of exposure that are estimated to be sufficient for target engagement based on the pharmacodynamic modeling. Consistent with prior preclinical data, YTX-7739 also showed clinically relevant drug concentrations in the cerebral spinal fluid (CSF).

The phase 1 MAD study is a placebo-controlled, randomized, double-blind study that is set to assess the safety, tolerability, and pharmacokinetics of once-daily oral administration of 2 doses of YTX-7739: 15 mg and 25 mg. The therapy will be given over the course of 14 to 28 days in 16 healthy male and female volunteers. The study is also evaluating measurements of plasma and CSF biomarker levels to assess pharmacodynamic activity.

Similar to the SAD study, it includes 2 cohorts of 8 subjects each, randomized to treatment or placebo in a 6:2 ratio. Yumanity noted that it anticipates the reporting of the results of the MAD study by the end of Q1 2021, with detailed clinical data from the phase 1 studies in healthy volunteers with YTX-7739 planned to be presented at a future medical conference.

“Recent advances in our understanding of the pathological processes underlying neurodegenerative diseases are providing the opportunities for innovative companies such as Yumanity to address this challenge with therapies that attack known disease pathways,” said Robert Scannevin, PhD, head of Discovery, Yumanity Therapeutics, in a statement. “Multiple lines of evidence indicate that misfolded alpha-synuclein is a strong risk factor for Parkinson’s disease. However, rather than targeting alpha-synuclein directly, we discovered that inhibiting the enzyme SCD could overcome alpha-synuclein toxicity, suggesting its potential as a therapeutic target.”

REFERENCE
Yumanity Therapeutics Provides Update on Its Lead Parkinson’s Disease Clinical Program, YTX-7739. News release. February 10, 2021. Accessed March 2, 2021. biospace.com/article/releases/yumanity-therapeutics-provides-update-on-its-lead-parkinson-s-disease-clinical-program-ytx-7739

Articles

Additionally, the therapy’s developer Yumanity Therapeutics announced the results of a single ascending dose study and enrollment in a multiple ascending dose study.

Phase 1b Study of Investigational Parkinson Disease Agent YTX-7739 Announced

The FDA has accepted a new drug application (NDA) from Avadel Pharmaceuticals for its investigational agent, FT218, in the treatment of excessive daytime sleepiness and cataplexy in adults with narcolepsy, the company announced.

The application for FT218, a once-nightly sodium oxybate formulation, has been given a Prescription Drug Use Fee Act (PDUFA) action date of October 15, 2021. The NDA is supported by the data from the phase 3 REST-ON study (NCT02720744)—conducted under a special protocol assessment agreement with the FDA—which met all 3 of its co-primary end points of change on Maintenance of Wakefulness Test (MWT) scores, Clinical Global Impression-Improvement (CGI-I) scores, and mean weekly cataplexy attacks.

Avadel noted in its release that it expects to present data from the study for the 3 end points, as well as a number of secondary end points and post-hoc analyses, at upcoming conferences in the first half of 2021.

“The FDA’s acceptance of our NDA for once-nightly FT218 and assignment of a PDUFA target action date of October 15 represents another important milestone on the path towards receiving approval. We are confident in our regulatory filing strategy and we look forward to working with the agency in our pursuit of bringing this important treatment to patients,” said Greg Divis, chief executive officer, Avadel, said in a statement.1 “If approved, FT218 will be the first and only once-nightly oxybate medication, a significant advancement to the twice-nightly regimen that has been required for nearly 20 years.”

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REST-ON study data were announced in May 2020 and showed that all 3 doses of FT218 assessed (9 g, 7.5 g, and 6 g) demonstrated highly significant, clinically meaningful improvements on MWT and CGI-I scores, as well as the average number of weekly cataplexy attacks.

The researchers involved in the study noted that the once-nightly 9-g FT218 showed highly statistically significant (

 <.001) and clinically meaningful improvement across all 3 co-primary end points compared to placebo. Additionally, the same dose was deemed generally well-tolerated with commonly known sodium oxybate adverse reactions occurring at low rates.

The commonly occurring adverse events (AEs) were nausea, vomiting, decreased appetite, dizziness, somnolence, tremor, and enuresis, occurring in 1.3%, 5.2%, 2.6%, 3.9%, 1.3%, and 9% of patients on treatment, respectively. Discontinuation occurred in 3.9% of patients on the 9-g dose.

The change from baseline to Week 13 in patients who used once-nightly 9-g FT218 on MWT was 10.82 minutes compared with 4.69 minutes for placebo (

 <.001). CGI-I, measured as the percentage of patients who were “much” or “very much” improved from baseline, was 72% and 31.6% for 9-g FT218 and placebo, respectively (

 <.001). The same dose also showed a reduction of 11.51 mean weekly cataplexy attacks compared with just 4.86 for the placebo group (

“It’s important to remember that FT218 was granted Orphan Drug Designation by the FDA based on the plausible hypothesis that it may be clinically superior to the twice-nightly formulation of sodium oxybate already approved by the agency for the same indication. If the FDA approves FT218 and grants Orphan Drug Exclusivity, then we would be awarded a 7-year period of market exclusivity in the US,” Divis said in his statement.

REFERENCE
1. Avadel Pharmaceuticals Announces FDA Acceptance of New Drug Application for FT218 in Adults with Narcolepsy for the Treatment of Excessive Daytime Sleepiness and Cataplexy. News release. March 1, 2021. Accessed March 2, 2021. https://www.globenewswire.com/news-release/2021/03/01/2184208/0/en/Avadel-Pharmaceuticals-Announces-FDA-Acceptance-of-New-Drug-Application-for-FT218-in-Adults-with-Narcolepsy-for-the-Treatment-of-Excessive-Daytime-Sleepiness-and-Cataplexy.html
2. Avadel Pharmaceuticals announces positive topline results from its pivotal phase 3 REST-ON trial of once-nightly FT218 for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. News release. April 27, 2020. Accessed March 2, 2021. https://www.globenewswire.com/news-release/2020/04/27/2022300/0/en/Avadel-Pharmaceuticals-Announces-Positive-Topline-Results-from-its-Pivotal-Phase-3-REST-ON-Trial-of-Once-Nightly-FT218-for-the-Treatment-of-Excessive-Daytime-Sleepiness-and-Cataple.html

Avadel’s investigational therapy for excessive daytime sleepiness and cataplexy in narcolepsy has an action date set for October 15, 2021.

FDA Accepts NDA for FT218 in Treatment of Narcolepsy Symptoms

Neurolief, a neurotechnology company, today announced that the FDA has cleared its noninvasive multichannel brain neuromodulation system, Relivion, for the at-home treatment of acute migraine in adults.

The Relivion system is a headset that offers precise and personalized treatment to patients via its 3 adaptive output channels, which target 6 branches of the occipital and trigeminal nerves. This methodology in turn releases neurotransmitters in the brainstem and modulates the networks associated with pain control, the company noted.

"The clearance by the FDA of the Relivion nonsignificant risk, noninvasive neuromodulation device for acute treatment of migraine is based on several randomized controlled trials that demonstrated effectiveness for achieving freedom from pain and freedom from a patient's most bothersome symptom chosen from photophobia, phonophobia, or nausea as well as pain relief within 2 hours of treatment,” Stewart J. Tepper, MD, professor of neurology, Geisel School of Medicine, Dartmouth, told 

. “The device combines neuromodulation of bilateral greater occipital nerves, supraorbital, and supratrochlear nerves, and this combination of inhibitory neuromodulation appears synergistic. Providers can look forward to access for another effective non-drug therapy for acute treatment of migraine."

“Patients will now have access to a highly effective, easy-to-use, non-invasive, and drug-free therapeutic option that will help them regain control of their lives,” he said in a statement.

Tepper was the principal investigator on the pivotal international RIME trial, which included 131 patients who met the 

International Classification of Headache Disorders

) criteria of migraine with or without aura, and was the basis for the approval of Neurorelief’s system. Patients in the trial were allowed to treat several migraine attacks during the course of the trial, using the device at the onset of migraine for up to a 1-hour session.

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The trial—a multi-center, prospective, randomized, double-blind, placebo-controlled clinical study—ultimately showed that 46% of those in the active treatment group achieved complete pain freedom at 2-hours post-treatment compared to only 11.8% in the control group. Pain relief was also significantly higher in the active group after 2 hours (active arm: 60%; control arm: 37%). Similarly, 75% of those in the active arm of the trial achieved complete freedom of the most bothersome symptom (MBS; defined as either phonophobia, photophobia, or nausea) within 2 hours of treatment, compared to 46.7% of those in the control group.

As for complete freedom of migraine symptoms, defined as freedom from both pain and MBS, those treated with neuromodulation from the Relivion after 2 hours had a significantly higher percentage of patients who achieved this (47.2%) compared to the control group (11.1%). No serious adverse events were reported.

The data on 55 patients were originally presented at the American Headache Society’s 2019 annual meeting.Those data showed that following 1-hour of treatment, pain decreased significantly more in the treatment group compared to the sham group at all time points (group difference: 1 hour, 41% [

= .02]). Additionally, ≥50% pain reduction responder rates were significantly higher in the treatment group than in the sham group after 1 hour (67% vs. 20%, respectively 

= .001), 2 hours (67% vs. 32%, respectively; 

= .02), and 24 hours (78% vs. 48%, respectively; 

Relivion was previously granted a CE Mark certification in Europe as a treatment device for migraine, and is currently in preparation for the market launch, Neurolief noted. In 2020, the device received Breakthrough Device designation from the FDA for the treatment of major depressive disorder, and the company anticipates submitting an application for major depressive disorder by 2022. Other neurological and neuropsychiatric indications, including ADHD and insomnia, are also being assessed.

Neuromodulation is clinically proven to alter brain function through targeted, delivery of currents to the central nervous system

Relivion is the first non-invasive multichannel brain neuromodulation system for treating neurological and neuropsychiatric disorders,"

Chris Richardson, chairman, Neurolief, told 

t offers precise, personalized care by delivering unparalleled stimulation to 6 branches of the occipital and trigeminal nerves via 3 adaptive output channels. This creates a cumulative effect by releasing neurotransmitters in the brainstem and modulate brain networks associated with the control of pain and mood. Effective treatment is realized without the risks and costs associated with invasive procedures and without the side effects associated with medications." 

"Our Physician Interface provides a quick and simple tool for: Optimizing treatment efficacy and patient outcomes, Sending instructions to the patient for setting and adjusting the Relivion treatment regimen, Remotely Monitoring patient condition, Enhancing treatment compliance, Empowering physicians to steer treatment according to simple treatment recommendations (based on AI), Additional reimbursement for physicians

REFERENCES
1. Relivion® Wearable Brain Neuromodulation Technology Cleared by FDA for the Treatment of Migraine. News release. March 2, 2021. Accessed March 2, 2021. https://www.biospace.com/article/releases/relivion-wearable-brain-neuromodulation-technology-cleared-by-fda-for-the-treatment-of-migraine
2. Neurolief Announces Positive Results From RIME Clinical Study of Its Brain Neuromodulation System for Treating Acute Migraine. January 6, 2021. Accessed March 2, 2021. https://www.businesswire.com/news/home/20210106005510/en/Neurolief-Announces-Positive-Results-From-RIME-Clinical-Study-of-Its-Brain-Neuromodulation-System-for-Treating-Acute-Migraine
3. Oved D, Tepper SJ. First Non-Invasive Combined Occipital & Trigeminal Nerve Stimulation Digital Therapeutics System for Treatment of Migraine: A Randomized, Sham-Controlled, Double-Blind Clinical Trial. Presented at AHS 2019 Annual Scientific Meeting; July 11–14, 2019. Philadelphia, PA. https://www.neurolief.com/wp-content/uploads/2019/07/American-Headache-Society2019-Abstract-Oved-Daniel-Stewart-Tepper.pdf

The headset system from Neurolief was approved based on the findings of a clinical trial of 131 patients with migraine who utilized the device in treatment sessions of up to 1 hour.

Relivion Noninvasive Neuromodulation System Cleared for Acute Migraine

Interim data from the phase 2 VISIONARY-MS trial (NCT03536559) suggest that Clene Nanomedicine’s investigational nanocatalytic agent CNM-Au8 demonstrates potential as a promoter of neurological improvement in patients with stable multiple sclerosis (MS) who are currently on disease-modifying therapy (DMT).

The analysis showed that patients treated with CNM-Au8 with an Expanded Disability Status Scale (EDSS) score of 2.0 or higher experienced clinically relevant improvements on a number of modified MS Functional Composite (MSFC) subscales compared with those patients with EDSS scores of 1.5 or lower, or the most mildly affected patients.

The data were presented virtually at the 

Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS)

, February 25-27, by Robert Glanzman, MD, FAAN, chief medical officer, Clene Nanomedicine.

“The takeaway here is that we’re seeing a brand-new therapeutic category,” Glazman told 

. “No one has been able to actually have nanocatalysts—we’re directly donating and receiving electrons to and from biological systems, and not just a few electrons, but thousands. I think [CNM-Au8] holds tremendous promise for all kinds of neurodegenerative diseases, including progressive MS.”

Glanzman added that the clinical community should be on the lookout for when the company eventually reveals unblinded data down the road for this therapy. He noted that VISIONARY-MS, while still ongoing, has faced a number of delays due to the ongoing pandemic like many other clinical trials, and hopes to resume enrollment in the later part of 2021.

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Those in the EDSS 2.0 or higher group experienced improvements equating to nearly 0.5 standard deviation (SD) above the baseline value for the most mildly affected patients, who were the comparator group, in the Symbol Digital Modalities Test (SDMT; 

 <.0001) as well as in Best Corrected Low-Contrast Letter Acuity (BC-LCLA; 

 = .0071). Additionally, improvements were observed in the 9-Hole Peg Test (9HPT) non-dominant (

 = .0050) and in the Timed 25-Foot Walk test (T25W; 

The change in the 6-component MSFC z-score—which included the SDMT, LCLA in both eyes, 9HPT with both dominant and nondominant hands, and T25W—was significantly improved for those with EDSS 2.0 or higher compared to the EDSS 1.0 or lower group (

In total, the 52 patients in the trial are on a number of DMTs, with 52% (n = 27) on a monoclonal antibody (alemtuzumab, natalizumab, rituximab, and ocrelizumab), 36.5% (n = 19) on an oral therapy (fingolimod, dimethyl fumarate, teriflunomide, thyroxine, and oral combinations), and 4% (n = 2) on an injectable (glatiramer acetate). The remaining 8% (n = 4) of patients were not actively on a DMT. The mean overall baseline EDSS score was 1.8 (SD, 1.5), with an average time from MS onset being 6.0 years (SD, 3.8).

Additionally, Clene presented preliminary results from the REPAIR-MS clinical trial (NCT03993171) which offer the first clinical evidence that demonstrates the catalytic effects of CNM-Au8 on key bioenergetic metabolites in MS (and Parkinson disease) brains. Those data revealed that the therapy increases the NAD+/NADH (nicotinamide adenine dinucleotide) ratio and AT (adenosine triphosphate) levels, as measured by percent change.

Glanzman and colleagues noted that the brain metabolic homeostasis observed with CNM-Au8 treatment may be neuroprotective; this hypothesis is currently being explored in both VISIONARY-MS and REPAIR-ALS phase 2 and Healey ALS Platform phase 3 studies. Full analyses of those data are expected to be conducted once the trials are completed.

“As VISIONARY-MS and REPAIR-MS continue to progress, we see consistent and complementary results,” Glanzman said in a statment.

 “Interim data from the REPAIR-MS program provide further evidence for CNM-Au8 to enter the brain and reverse bioenergetic failure, a key driver in the pathophysiology of MS and other neurodegenerative diseases.”

VISIONARY-MS, Clene noted in its release, represents the first efficacy study for a completely novel therapeutic category. CNM-Au8 is a nanotherapeutic agent designed to provide bioenergetic, catalytic support to neurons and oligodendroglia precursor cells for neuroprotection and improved remyelination in MS.

“These mechanistic results provide important support for the updated, blinded interim VISIONARY data analysis, which suggest that CNM-Au8 has the potential to drive clinically meaningful improvements in recognized MS functional endpoints when administered in addition to standard of care,” Glanzman continued in the statement. “We look forward to the continued advancement of these trials.”

For more coverage of ACTRIMS Forum 2021, 

REFERENCES
1. Glanzman RL, Beadnall H, Barnett M, et al. VISIONARY-MS: Update to a Phase 2 clinical trial of catalytic gold nanocrystals, CNM-Au8, for the treatment of chronic optic neuropathy. Presented at ACTRIMS Annual Forum; February 25-27, 2021. Abstract P050.
2. Clene Nanomedicine Presents Updated Interim Data from Phase 2 Multiple Sclerosis Programs at ACTRIMS Forum 2021. News release. February 25, 2021. Accessed February 26, 2021. https://finance.yahoo.com/finance/news/clene-nanomedicine-presents-updated-interim-123100727.html
3. Glanzman RL, Rin J, Greenberg B, et al. Effects of Nanocatalysis on CNS Bioenergetic Markers in Patients Treated with CNM-Au8: Interim Results from Two Phase 231Phosphorous Imaging Studies. Presented at ACTRIMS Annual Forum; February 25-27, 2021. Abstract P043.

Clene Nanomedicine’s nanocatalyst agent CNM-Au8 displayed significant improvements in patients with EDSS scores of 2.0 or higher compared to those with EDSS scores of 1.5 or lower.

Matt Hoffman

Articles

Phase 1b Study of Investigational Parkinson Disease Agent YTX-7739 Announced

FDA Accepts NDA for FT218 in Treatment of Narcolepsy Symptoms

Relivion Noninvasive Neuromodulation System Cleared for Acute Migraine

CNM-Au8 Displays Positive Interim Results in Multiple Sclerosis